Abstract Although the genes that drive the development of myeloid blood cancers have largely been defined, there are currently very few effective targeted therapies for these diseases. This illuminates the need to exploit the molecular understanding that has been gained in the last decade through cancer exome sequencing to identify unique therapeutic vulnerabilities in myeloid malignancies. We recently identified the mechanism by which mutant calreticulin (CALR) is oncogenic in myeloproliferative neoplasms (MPN), a subtype of myeloid blood cancers. This work revealed the following key findings: (i) The thrombopoietin receptor, MPL is absolutely required for mutant CALR-mediated hematopoietic transformation, (ii) mutant CALR activates JAK/STAT signaling downstream of MPL, and (iii) the C-terminus of mutant CALR is required for its oncogenic activity, through facilitating a physical interaction between mutant CALR and MPL. However, the mechanism by which the binding between mutant CALR and MPL activates pathogenic MPL signaling remains unknown. I will seek to answer this in Specific Aim 1 of this proposal. Although such dissection of the molecular mechanisms underlying oncogenic proteins in myeloid malignancies is a crucial step in developing rational approaches to therapy, it is perhaps even more critical to identify unique, non-oncogenic molecular vulnerabilities in cells transformed by these oncogenes. In recent years, the unfolded protein response (UPR) has emerged as a major regulator of cancer cell survival. The UPR orchestrates the restoration of ER function to help cancer cells adapt to microenvironmental changes, including those that disrupt redox, calcium, and metabolic homeostasis. As an endoplasmic reticulum (ER) chaperone, CALR is a critical UPR effector. However, the role of the UPR in mutant CALR-driven MPN has yet to be studied. In Specific Aim 2 of this proposal, I will determine whether mutant CALR-transformed cells are dependent on the UPR for survival, and whether this pathway can be targeted for therapeutic gain in MPN. In the R00 phase (Specific Aim 3) of this proposal, I will employ the insight gained through the study of the UPR in MPN to investigate whether this pathway is important in more aggressive myeloid blood cancers such as acute myeloid leukemia (AML). Although the UPR has been demonstrated to play a role in myeloid leukemogenesis, it has only been interrogated in a limited number of genetic subtypes of AML. Despite the fact that many AML mutations are associated with altered metabolic homeostasis and likely engage the UPR as a result, the role of this pathway in the context of such mutations has yet to be explored. In an entirely new line of study, I will interrogate the UPR specifically in genetic subsets of AML where cellular metabolism is dysregulated, and determine whether targeting this pathway represents a new therapeutic avenue in the treatment of AML.